1. Field of the Invention
This invention relates to the formation of guest/host (cyclodextrin) inclusion complex microaggregates and the non-inclusion solubilization of water-insoluble compounds within such aggregates, as well as methods for solubilizing and stabilizing the microaggregates and cyclodextrin complexes of two or more drugs where at least one drug forms an inclusion complex with cyclodextrin and at least one other drug forms a non-inclusion complex with the inclusion complex formed.
2. Background Art
Cyclodextrins are a group of structurally related saccharides that are formed by enzymatic cyclization of starch by a group of amylases termed glycosyltransferases. Cyclodextrins are cyclic oligosaccharides, consisting of (α-1,4)-linked α-D-glucopyranose units, with a somewhat lipophilic central cavity and a hydrophilic outer surface. Due to lack of free rotation about the bonds connecting the glucopyranose units, the cyclodextrins are not perfectly cylindrical molecules but are cone-shaped. The primary hydroxyl groups of the sugar residues are located on the narrow end of the formed cone while the wider face contains the secondary hydroxyl groups.
The most common naturally occurring cyclodextrins are α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin consisting of 6, 7 and 8 glucopyranose units, respectively. Of these three derivatives, β-cyclodextrin appears to be the most useful pharmaceutical complexing agent due to its cavity size, availability, low cost and other properties.
The natural cyclodextrins, in particular β-cyclodextrin, have limited aqueous solubility and their complex formation with lipophilic drugs often result in precipitation of solid drug-cyclodextrin complexes. Thus, the solubility of β-cyclodextrin in water is only about 18.5 mg/mL at room temperature. This low aqueous solubility is, at least partly, associated with strong intermolecular hydrogen bonding in the cyclodextrin crystal lattice. Substitution of any of the hydrogen bond-forming hydroxyl groups, even by hydrophobic moieties such as methoxy groups, will increase the aqueous solubility of β-cyclodextrin.
In addition, since these manipulations frequently produce large numbers of isomeric products, chemical modification can transform the crystalline cyclodextrins into amorphous mixtures, increasing their aqueous solubility. For example, isomeric mixtures of 2-hydroxypropyl-β-cyclodextrin are obtained by treating a base-solubilized solution of β-cyclodextrin with propylene oxide. The aqueous solubility of 2-hydroxypropyl-β-cyclodextrin is over 60 g/100 mL. These cyclodextrin systems resemble, therefore, other pharmaceutical starches, such as hydroxypropyl cellulose, in terms of the complexity of their composition. Both the molar substitution, i.e., the average number of propylene oxide molecules that have reacted with one glucopyranose unit, and the location of the hydroxypropyl groups on the β-cyclodextrin molecule will affect the complexation properties of the 2-hydroxypropyl-β-cyclodextrin mixture. Other cyclodextrin derivatives of current pharmaceutical interest include the analogous hydroxypropyl derivatives of α- and γ-cyclodextrin, sulfoalkyl ether cyclodextrins such as sulfobutylether β-cyclodextrin, alkylated cyclodextrins such as the randomly methylated β-cyclodextrin, and various branched cyclodextrins such as glucosyl- and maltosyl-β-cyclodextrin.
In aqueous solutions cyclodextrins form complexes with many drugs, as well as other molecules, which possess somewhat hydrophobic moieties capable of entering the somewhat lipophilic central cavity, through a process in which the water molecules located in the cavity are replaced by this hydrophobic moiety. In some cases, small lipophilic water-insoluble drugs (or other small lipophilic compounds) are completely encapsulated by the cyclodextrin molecule, but in most cases the drug molecules are too large and thus will only be partly encapsulated by the cyclodextrin molecule. The drug molecule is called the guest molecule and the cyclodextrin molecule the host molecule. The cyclodextrin cavity is relatively hydrophobic due to the presence of the skeletal carbons and ethereal oxygens that comprise the cavity. Since the water molecules located inside the cavity cannot satisfy their hydrogen-bonding potential, they are of higher enthalpy than bulk water molecules located in the solution. The main driving force for complex formation, at least in the case of β-cyclodextrin and its derivatives, appears to be the release of these enthalphy-rich water molecules from the cavity, which lowers the energy of the system. Once included in the cyclodextrin cavity, the guest molecules may be dissociated through complex dilution, by replacement of the included guest by some other suitable molecule (such as dietary lipids or bile salts in the GI tract) or, if the complex is located in close proximity to a lipophilic biological membrane (such as the mucosal membrane of the GI tract), the guest may be transferred to the matrix for which it has the highest affinity. Importantly, since no covalent bonds are formed or broken during the drug-cyclodextrin complex formation, the complexes are in dynamic equilibrium with free drug and cyclodextrin molecules.
One of the main obstacles of pharmaceutical applications of cyclodextrins is their complexation efficiency. For a variety of reasons, including toxicological considerations, formulation bulk and production cost, it is important to use as little cyclodextrin as possible in pharmaceutical preparations. Unfortunately, the complexation efficiency of cyclodextrins is frequently rather low, in which case large amounts of cyclodextrin are needed to complex relatively small amounts of drug. Common pharmaceutical additives, such as surfactants, buffer salts, preservatives and organic solvents, can reduce the efficiency even further (T. LOFTSSON, O. STEFANSDOTTIR, H. FRIDRIKSDOTTIR and O. GUDMUNDSSON: Interactions between preservatives and 2-hydroxypropyl-β-cyclodextrin. Drug Devel. INd. Pharm.; 18, 1477–1484, 1992; T. LOFTSSON and M. E. BREWSTER: Pharmaceutical applications of cyclodextrins. 1. Drug solubiization and stabilization. J. Pharm. Sci.; 85, 1017–1025, 1996). Normally solid drug-cyclodextrin complexes contain less that 5 to 10% of the drug. It is therefore important to develop methods that can be applied to enhance the complexation efficiency of cyclodextrins. In the past, the following methods have been applied in an effort to enhance the complexation efficacy of cyclodextrins, all of which assume that cyclodextrins interact with drug molecules on molecular bases through formation of inclusion complexes without further association or aggregation (T. LOFTSSON and M. E. BREWSTER: Cyclodextrins as Pharmaceutical Excipients. Pharmaceutical Technology Europe; 9, 26–34, 1997):
Unionized drugs usually form more stable cyclodextrin complexes than their ionic counterparts. However, it is sometimes possible to enhance cyclodextrin solubilization of ionizable drugs by appropriate pH adjustments (R. KRISHNAMOORTHY AND A. K. MITRA: Complexation of weak acids and bases with cyclodextrins: Effects of substrate ionization on the estimation and interpretation of association constants, Int. .J. Pharm. Advances, 1, 330–343, 1996; T. LOFTSSON AND N. BODOR: Effects of 2-hydroxypropyl-β-cyclodextrin on the aqueous solubility of drugs and transdermal delivery of 17β-estradiol, Acta Pharm.Nord., 1, 185–194; 1989; E. REDENTI, L. SZENTE AND J. SZEJTLI: Cyclodextrin Complexes of Salts of Acidic Drugs. Thermodynamic Properties, Structural Features, and Pharmaceutical Applications. J. Pharm. Sci., 90, 979–986, 2001). In this case the solubilization is increased due to increased intrinsic solubility of the drug obtained through ionization of the drug molecule. Furthermore, formation of water-soluble salts between a basic drug and an organic acid (such as lactic acid), or an acidic drug and organic base (such as tromethamine) can enhance the complexation due to lowering of the melting point of the solid drug which in turn increases the intrinsic solubility of the drug. See also BADWAN ET AL. U.S. Pat. No. 5,646,131.
Addition of certain low molecular weight acids, such as acetic, citric, malic, or tartaric acid, to aqueous complexation media can enhance cyclodextrin solubilization of basic drugs as well as increase complexation efficiency (E. REDENTI, L. SZENTE AND J. SZEJTLI: Drug/Cyclodextrin/Hydroxy Acid Multicomponent Systems. Properties and Pharmaceutical Applications. J. Pharm. Sci., 89, 1–8, 2000). Enhanced complexation is obtained through formation of free (i.e., un-aggregated) drug-hydroxy acid-cyclodextrin ternary complexes with basic drugs. In all cases the drug has to be a proton acceptor capable of forming an ion pair or salt with the acid. BADWAN ET AL., in U.S. Pat. No. 5,646,131, describe a method for enhancing the solubilization of a drug which is insoluble or sparingly soluble in water by combining the drug in water with cyclodextrin and a saturated or unsaturated C2–C6 carboxylic acid having 1 to 3 COOH groups and 0 to 4 OH groups, provided that when the acid has only one COOH group, it must bear at least one OH group, or a salt of the acid, the weight ratio of cyclodextrin to carboxylic acid being from 1:50 to 5:1. Preferred are citric acid, glutaric acid, lactic acid, tartaric acid and their salts. Basic drugs are of particular interest.
Water-soluble Polymers
It has been shown that various pharmaceutical polymers, such as water-soluble cellulose derivatives and other rheological agents, can form complexes with cyclodextrins and that such complexes possess physicochemical properties distinct from those of individual cyclodextrin molecules (THORSTEINN LOFTSSON: Cyclodextrin/drug complexation, U.S. Pat. No.: 5,324,718 (Filed: Jul. 14, 1992; Issued: Jun. 28, 1994); THORSTEINN LOFTSSON: Cyclodextrin Complexation, U.S. Pat. No. 5,472,954 (Filed: May 11, 1994; Issued: Dec. 5, 1995)). In aqueous solutions, water-soluble polymers increase the solubilizing effect of cyclodextrins on various hydrophobic drugs by increasing the apparent stability constants of the drug-cyclodextrin complexes. See also T. LOFTSSON AND H. FRIDRIKSDOTTIR: The effect of water-soluble polymers on the aqueous solubility and complexing abilities of β-cyclodextrin. Int. J. Pharmaceutics, 163, 115–121, 1998; and B. POSE-VILARNOVO ET AL., Journal of Thermal Analysis and Calorimetry, Vol. 68, 657–667, 2002.
Combination Methods
Finlly, it is often possible to enhance cyclodextrin complexation even further by using several different methods simotaneously to enhance the cyclodexrin complexation (T. LOFTSSON, T.K. GUDMUNDSDOTTIR AND H. FRIDRIKSDOTTIR: The Influance of Water-Soluable Polymers and pH on Hydroxypropyl-β-Cyclodextrin of Drugs. Drug Devel. Ind. Pharm., 22, 401–405, 1996).